Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:52]=1[C:63]([NH2:65])=[O:64]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:50][C:51]2[C:52]([C:63](=[O:64])[NH2:65])=[C:53]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:54]=[CH:55][CH:56]=2)=[O:16])[N:13]=1)(=[O:7])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1c(N)cccc1-c1ccccc1
Reactant: CC(C)(C)NS(=O)(=O)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NS(=O)(=O)c1nc(C(=O)Nc2cccc(-c3ccccc3)c2C(N)=O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
To a solution of 2-(N-tert-butylsulfamoyl)thiazole-4-carboxylic acid (0.56 g, 2.1 mmol) in DCM (50 mL) was added HATU (1.41 g, 2.8 mmol) and DIPEA (1.04 ml, 5.6 mmol). The reaction mixture was stirred at room temperature for 1 h and then 3-aminobiphenyl-2-carboxamide (from example 218, 0.3 g, 1.4 mmol) was added. The resulting solution was stirred for an additional 16 h. After this time, the reaction mixture was washed with water, dried, filtered and concentrated under reduced pressure to yield a residue. The residue was purified by silica gel chromatography (30% EtOAc in hexane) to provide 2-(N-tert-butylsulfamoyl)-N-(2-carbamoylbiphenyl-3-yl)thiazole-4-carboxamide (0.11 g, 17% yield) as white solid. LCMS Method V: retention time 1.85 min; [M+1]=459.2.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.[F:35][C:36]([F:46])([F:45])[C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O.C([BH3-])#N.[Na+]>CO>[CH3:2][O:3][C:4]1[C:5]2[N:12]=[C:11]([NH:13][C:14]([N:16]3[CH2:17][CH2:18][N:19]([CH2:40][C:39]4[CH:42]=[CH:43][CH:44]=[C:37]([C:36]([F:35])([F:45])[F:46])[CH:38]=4)[CH2:20][CH2:21]3)=[O:15])[S:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCNCC3)nc12
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1ncnc2sc(NC(=O)N3CCN(Cc4cccc(C(F)(F)F)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
A solution of piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide hydrochloride (2 g, 6.0 mmol) in methanol (200 mL) was treated with N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The mixture was stirred at 25° C. for 10 min until a clear solution formed. At this time, the reaction was treated with acetic acid (1.75 mL, 30.6 mmol), 3-trifluoromethy-benzaldehyde (2.4 mL, 17.9 mmol) and sodium cyanoborohydride (1.1 g, 17.7 mmol). This mixture was stirred at 25° C. overnight. The reaction was then concentrated in vacuo and partitioned between methylene chloride and an aqueous phosphate buffer (pH=7). The organics were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo to give a solid. This solid was dissolved in methanol and absorbed onto silica gel (4 g). ISCO chromatography (330 g, Silica, gradient elution 5/95 methanol/methylene chloride) afforded 4-(3-trifluoromethyl-benzyl)-piperazine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (1.56 g, 58%) as a white solid; LRMS for C19H19F3N6O2S (M+H)+ at m/z=453. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]2[O:18][CH2:17]2)=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:16]([OH:18])[CH2:17][NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+:13]([O-:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: [O-][n+]1cc(OCc2ccccc2)ccc1C1CO1
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)c[n+]1[O-]

Procedure:
To 0.50 g. (0.0042 mole) of [5-benzyloxy-2-(1,2-epoxyethyl)pyridine N-oxide] in 20 ml. of methanol was added 0.5 ml. tert-butylamine and the resulting mixture heated to the reflux temperature for 4 hours. Solvent and excess tert-butylamine were removed in vacuo to give 280 mg. (43%) of the desired product after recrystallization from ether/ethyl acetate; m.p. 148°-150° (dec.). Mass spec (70 eV) m/e 300 (M-16), m/e 243 [MH2NC(CH3)3); NMR (DMSO d6)delta 7.90 (d, 1H, H6), 7.30 (m, 6H, benzyl C6H5 and H4), 7.00 (m, 1H, H3), ##STR14## and 1.13 [s, 9H, C(CH3 ]; ir (KBr) 1171 (N+ -O-).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Br[CH2:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22](=[O:27])[CH2:21][N:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C@@H:9]([NH:16][C:17](=[O:19])[CH3:18])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)CBr
Reactant: CC(=O)N[C@H]1CCC2(CCNCC2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H]1CCC2(CCN(CC(=O)C(C)(C)C)CC2)c2ccccc21
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A suspension of the piperidine (B5) (24 mg, 0.09 mmol), 1-bromo-3,3-dimethylbutan-2-one (13.5 mg, 0.08 mmol) and sodium carbonate (32 mg, 0.3 mmol) in DMF (1 ml) was stirred at 50° C. in a sealed vial for 16 hours. The mixture was cooled and carefully neutralized with TFA and purified by reverse phase HPLC to give the title compound no. 19 as a TFA salt. LC-MS: m/e=357.30 (M+H). Rt=1.61 min. 1H-NMR (500 MHz, DMSO-d6): 9.60 (br. s, 1H), 8.21 (d, 1H), 7.44 (d, 1H), 7.32 (t, 1H), 7.20 (t, 1H), 7.16 (d, 1H), 4.92 (q, 1H), 4.60 (d, 2H), 3.26 (m, 4H), 2.35 (m, 2H), 2.04 (dd, 1H), 1.87 (s, 3H), 1.80 (m, 3H), 1.71 (d, 1H), 1.63 (m, 1H), 1.16 (s, 9H).
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(C(C)C)C(C)C)C.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(OCC)(=O)C>[N:17]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[NH:8][C:3]1[C:2]([S:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)CCS
Reactant: Brc1cccnc1Nc1nc2cccnc2s1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)CCSc1cccnc1Nc1nc2cccnc2s1
Temperature: 95 °C
Yield: 87.2 %

Procedure:
A mixture of N-(3-bromopyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine (0.55 g, 1.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.052 g, 0.090 mmol), Pd2dba3 (0.041 g, 0.045 mmol), methyl 3-mercaptopropanoate (0.21 mL, 1.88 mmol), N-ethyl-N-isopropylpropan-2-amine (0.62 mL, 3.60 mmol), and dioxane (40 mL) was heated to 95° C. under nitrogen. Cooled to ambient temperature and filtered the solids. Concentrated and purified by MPLC (Biotage) eluting with 1:1 hexane:ethyl acetate to afford the title compound (0.541 g, 87% yield) as a dark yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([N:29]=[C:30]=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 32 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,5-Bis(trifluoromethyl)phenyl isocyanate in a similar manner as described in Example 1.53, providing 21.5 mg (32%) of Compound 82: LCMS m/z (%)=495 (M+H37Cl, 41), 493 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 9.18 (s, 1H), 8.31 (s, 2H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.59 (d, J=2 Hz, 1H), 7.36 (d=8 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C@@:23]2([CH3:24])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:25])=[CH:9][C:8](=[O:26])[CH:7]=1)(=O)C.CO.[OH-].[K+]>C(Cl)Cl>[OH:4][CH2:5][C:6]1[C@@:23]2([CH3:24])[C:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:25])=[CH:9][C:8](=[O:26])[CH:7]=1
Reactant: CC(=O)OCC1=CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: C[C@]12C(CO)=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 87.6 %

Procedure:
2.2 g of 1-acetoxymethylandrosta-1,4-diene-3,17-dione is stirred under argon gas atmosphere in 20 ml of methylene chloride and 25 ml of methanol with 250 mg of potassium hydroxide at 0° to 5° C. for 5 hours. The mixture is then neutralized with acetic acid, concentration, and precipitated into water. The product is suctioned off, washed with water, and dried. Recrystallization from acetone/hexane yields 1.7 g of 1-hydroxymethylandrosta-1,4-diene-3,17-dione, mp 201°-202° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=O.P(Cl)(Cl)([Cl:18])=O.C(N(CC)CC)C.C(#N)C>C(OCC)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]=[C:3]([Cl:18])[C:2]([F:15])([F:14])[F:1])=[CH:7][CH:8]=1
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(N=C(Cl)C(F)(F)F)cc1
Temperature: 82 °C
Yield: 117.6 %

Procedure:
Ten grams (45.6 mmol) of 2,2,2-trifluoro-N-(4-methoxyphenyl)acetamide, 4.92 g (32.0 mmol) of phosphorus oxychloride, 9.23 g (91.2 mmol) of triethylamine, and 50 ml of acetonitrile were introduced into a 200 ml flask and reacted for 19 hours while being refluxed (82° C.). After the reaction, the reaction solution was cooled to room temperature, 30 ml of ethyl acetate was added thereto, and the precipitate was then filtered off. The filtrate was subjected to solvent removal by evaporation, and the crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 8.94 g of N-(4-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride as a yellow liquid (yield: 82.5%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[CH3:10][NH:11][CH2:12][CH2:13]O.[CH2:15]=[O:16]>>[CH:7]1[N:8]=[CH:9][C:4]([C:1]([CH2:2][CH2:10][NH:11][CH2:12][CH2:13][CH2:15][OH:16])=[O:3])=[N:5][CH:6]=1
Reactant: CNCCO
Reactant: CC(=O)c1cnccn1
Reactant: C=O
Product: O=C(CCNCCCO)c1cnccn1

Procedure:
2-acetylpyrazine (122 mg), methylhydroxyethyl amine (75 mg), and paraformaldehyde (40 mg) were reacted at 130° C. for 2 hours.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:30]=[CH:29][C:28]2[C:19](=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:30]=[CH:29][C:28]3[C:19](=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:18]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: BrCc1ccc2cc3ccccc3cc2c1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2cc3ccccc3cc2c1
Temperature: 60 °C

Procedure:
Sodium hydride (50% dispersion in oil, 1.37 g, 28.6 mmol, 1.1 eq) was added to a DMF solution (50 mL) containing 2-n-butyl-4-chloroimidazole-5-carboxaldehyde (prepared as in European Patent Application Number 89100144.8, published 7.19.89) (4.85 g, 26.0 mmol, 1.0 eq). The contents were heated with stirring at 60° C. until everything was dissolved. The reaction was then cooled to 0° C. and a DMF solution (75 mL) of 2-bromomethylanthracene (entire contents from the previous step: 7.77 g of impure material, theoretically 26.0 mmol, 1.0 eq) was added and the entire contents stirred at room temperature overnight. The solvent was removed in vacuo and the residue flash chromatographed in 9:1 toluene/ethyl acetate to 75:25 toluene/ethyl acetate to yield 3.73 g of an amber glass. This material could not be crystallized and was used without further purification for the next step. NMR (CDCl3): δ 9.80 (s, 1H); 8.40 (s, 1H); 8.33 (s, 1H); 7.98 (m, 3H); 7.48 (m, 3H); 7.23 (m, 1H); 5.72 (s, 2H); 2.79 (t, 2H, J=7Hz); 1.69 (t of t, 2H, J=7,7Hz); 1.33 (t of q, 2H, J=7,7Hz); 0.84 (t, 3H, J=7Hz). ##STR56##
Reaction SMILES: [CH2:1]([S:8][C:9](=[S:15])[NH:10][CH2:11][C:12](Cl)=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[Cl:21]C1C=CC=CC=1>>[CH2:1]([S:8][C:9]1[S:15][C:12]([CH2:13][Cl:21])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccccc1
Reactant: C=C(Cl)CNC(=S)SCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: ClCc1cnc(SCc2ccccc2)s1
Temperature: 5.5 °C
Reaction time: 0.33 h

Procedure:
Under a slight stream of nitrogen, 35.8 g of (2-chloro-allyl)-dithiocarbamic acid benzyl ester and 31.8 g of sodium hydrogen carbonate are placed in 250 ml of chlorobenzene. The mixture is then cooled to 5-6° C. The apparatus is flushed thoroughly with nitrogen. Then 28.2 g of sulfuryl chloride are added in the course of 120 minutes in such a manner that the temperature can be maintained at 5-10° C. When the addition is complete, stirring is carried out for about 20 minutes. The reaction mixture is filtered off with suction, the filtration residue is washed with 20 ml of chlorobenzene, and the filtrate is thoroughly degassed in vacuo at 20-25° C. Then the solvent is removed by distillation at 30° C. under reduced pressure. 90 ml of hexane are added to the residue. Seeding is carried out, then the mixture is stirred at about 0° C. and about 0.8 g of hydrogen chloride gas is introduced until the solution will take up no more gas. The mixture is stirred for a further 15 minutes, the crude product is filtered off at 0-5° C., and the filtration residue is washed with 10 ml of hexane and dried in vacuo. In that manner 2-benzylsulfanyl-5-chloromethyl-thiazole is obtained in the form of the hydrochloride.
Reaction SMILES: Cl.N1C=CC=CC=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]=2[CH:28]=1>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]=2[CH:28]=1
Reactant: COc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Temperature: 190 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
Pyridine hydrochloride (4.4 g, 37.8 mmol) was heated to 190° C. 8-bromo-2-methoxy-6H-dibenzo[c,h]chromene (1.29 g, 3.8 mmol) was added and the reaction was stirred at 190° C. After four hours, the reaction was cooled to room temperature and diluted with water. A precipitate formed which was collected by filtration and purified by flash column chromatography to yield 8-bromo-6H-dibenzo[c,h]-chromen-2-ol (697 mg, 56%).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.Cl.[CH2:33]([N:35]([CH:38](C)C(O)=O)[CH2:36][CH3:37])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][N:29]([C:3](=[O:5])[CH2:2][CH2:38][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])[CH2:28][CH2:27]2)[N:10]=1
Reactant: CCN(CC)C(C)C(=O)O
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Agent: Cl
Product: CCN(CC)CCC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 20 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 11, and diethylaminopropionic acid hydrochloride (Aldrich), to give 1-[4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-diethylamino-propan-1-one. HRMS, observed: 455.2769; Calcd for (M+H)+: 455.2765.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])(=[O:9])=[O:8])=[N+]=[N-].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH2:11][C:12]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:16][C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])=[N:14][N:13]1[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])(=[O:9])=[O:8]
Reactant: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN=[N+]=[N-])(c2ccccc2)S1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)NC1=NN(C(=O)C(C)(C)C)C(CNS(=O)(=O)CCCN)(c2ccccc2)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Next, the resulting N-[5-(3-azidopropanesulfonylamino-methyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide was dissolved in THF (53 mL), and water (10.6 mL) and triphenylphosphine (1.24 g, 4.73 mmol) were added, then the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and water and saturated aqueous sodium hydrogencarbonate were added, then the mixture was extracted with ethyl acetate. The organic layer was extracted with aqueous hydrochloric acid, and the aqueous layer was made basic by adding saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The resulting organic layer was concentrated under reduced pressure to give N-[5-(3-aminopropanesulfonylaminomethyl)-4-(2,2-dimethylpropionyl)-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl]-2,2-dimethylpropanamide (1.29 g, 89%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([OH:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO.CCCCCC>[OH:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ncccc1O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ncccc1O
Reaction time: 8 h
Yield: 41 %

Procedure:
3-Hydroxypicolinic acid (5.0 g) was dissolved in 350 ml of toluene and 100 ml of methanol. A 2 M solution (25 ml) of trimethylsilyldiazomethane in hexane was added dropwise to the solution, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was concentrated under the reduced pressure. Methylene chloride (100 ml) and water (100 ml) were then added to the concentrate to conduct extraction. The aqueous layer was then extracted with methylene chloride. The organic layer was dried over magnesium sulfate, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate-hexane) to give 2.3 g (yield 41%) of methyl 3-hydroxypicolinate.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1([CH3:50])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[C:39]([C:44]#[N:45])=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH3:49])[CH:20]=2)[O:15]1>O>[CH3:13][C:14]1([CH3:50])[CH2:23][CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[C:29](=[O:30])[N:28]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=5[C:44]5[NH:3][C:4](=[O:7])[O:5][N:45]=5)=[CH:34][CH:33]=4)[C:27]([CH2:46][CH2:47][CH3:48])=[N:26][C:25]=3[CH3:49])[CH:20]=2)[O:15]1
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)c(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1nc(C)c(-c2ccc3c(c2)CCC(C)(C)O3)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A mixture of hydroxylammonium chloride (1.37 g), sodium hydrogen carbonate (1.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.58 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.28 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.46 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])C(S)=[CH:7][C:3]=1[C:4](O)=O.[OH-].[Na+].[S:15](OC)(OC)(=O)=O.Cl.[CH2:23]([OH:25])[CH3:24]>O>[Cl:11][C:9]1[CH:10]=[C:2]([Cl:1])[C:3]([CH3:7])=[CH:4][C:24]=1[C:23]([OH:25])=[S:15]
Reactant: O=C(O)c1cc(S)c(Cl)cc1Cl
Reactant: COS(=O)(=O)OC
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(O)=S)c(Cl)cc1Cl

Procedure:
A stirred solution of 2,4-dichloro-5-mercaptobenzoic acid (30 g.; 0.135 mole) in 50% aqueous ethanol (500 ml.) and sufficient 10N sodium hydroxide to attain a pH of 9 is heated to reflux and treated dropwise with dimethyl sulfate (26 g.; 0.206 mole) during a two hour period. The pH is maintained at 9 during the addition. The reaction mixture then is cooled, diluted with water (1 liter) and acidified with dilute hydrochloric acid, yielding 30 g.; (94%) of 2,4-dichloro-5-methylthiobenzoic acid, m.p. 187° C. after recrystallization from nitromethane.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([OH:11])[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C:5]1[CH:10]=[C:9]([O:11][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([Cl:12])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(O)c(Cl)cn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Oc1cc(OC(=O)c2ccccc2)c(Cl)cn1
Yield: 96 %

Procedure:
The general procedure of Example 21 was followed using 200 mg of 2-acetoxy-5-chloro-4-hydroxypyridine, 0.15 ml of benzoyl chloride and 0.74 ml of triethylamine and 20 ml of acetonitrile, thereby giving 300 mg of the title compound in a yield of 96%.